SPG11 was first reported in relation to autosomal recessive hereditary spastic paraplegia 11 (HSP11) in 2007 (HStevanin G, et al., 2007, PMID: 17322883). HSP11 is clinically characterized by the progressive spasticity of the lower limbs, thin corpus callosum and cognitive impairment. White matter alterations may be part of the clinical phenotype. HSP11 is a complex disorder that occurs along a spectrum of disease including cases with wither slowly progressive juvenile amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease, due to overlapping variants with a loss of function mechanism. As per ClinGen lumping and splitting criteria, these diseases were considered under the lumped entity of HSP11. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Thirty-six variants have been curated (including frameshift, nonsense, and splice variants), from 18 probands in 3 publications (PMIDs: 17322883, 20110243, 26556829). Cosegregation of variants with disease was reported in at least 26 family members as well. Additional evidence is available in the literature but the maximum score for genetic evidence was reached. Experimentally, this gene-disease relationship is supported by its biochemical function in autophagic lysosome reformation (PMID: 25365221), which it shares with spastizin, another HSP related gene, with similarities in their expression and localization patterns that could account for their overlapping clinical phenotypes (PMID: 21545838), and is disrupted in patient cells (Renvoisé B, et al., 2014, PMID: 24999486). as a prominent guanine nucleotide exchange factor (GEF) for the small GTPase Rab5 (PMID: 12837691). A knockout mouse recapitulates the full range of symptoms associated with SPG11 mutations observed in HSP, ALS and CMT patients (PMID: 28237315) and 2D culture systems and 3D human brain organoids have shed light on the neurodevelopmental mechanisms underlying disease pathology (PMID: 30476097). In summary, there is definitive evidence to support this gene-disease relationship.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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